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1.
BMC Endocr Disord ; 21(1): 133, 2021 Jun 28.
Article in English | MEDLINE | ID: mdl-34182970

ABSTRACT

BACKGROUND: To evaluate the effect of nicotinamide prior to streptozotocin-induced (STZ) diabetes in baroreflex sensitivity and cardiovascular autonomic modulation, and its association with hemodynamics and metabolic parameters. METHODS: Methods: Male Wistar rats were divided into control (Cont) and STZ-induced diabetes (Diab). Half of the rats from each group received a single dose of nicotinamide (100 mg/Kg) before STZ injection (Cont+NicA and Diab+NicA). All groups were followed-up for 5 weeks. RESULTS: Body weight loss of more than 40% was observed in Diab throughout the period (Diab: 271.00 ± 12.74 g; Diab+NicA: 344.62 ± 17.82). Increased glycemia was seen in Diab rats (541.28 ± 18.68 mg/dl) while Diab+NicA group had a slight decrease (440.87 ± 20.96 mg/dl). However, insulin resistance was observed only in Diab. In relation to Cont, heart rate, mean blood pressure and diastolic function were reduced when compared to Diab, together with parasympathetic modulation and baroreflex sensitivity. All of these parameters were improved in Diab+NicA when compared to Diab. Improved baroreflex sensitivity and parasympathetic modulation were correlated with glycemia, insulin resistance, and body weight mass. Additionally, Diab+NicA group increased survival rate. CONCLUSIONS: Results suggest that the association of nicotinamide in STZ-induced diabetic rats prevents most of the expected derangements mainly by preserving parasympathetic and baroreflex parameters.


Subject(s)
Autonomic Nervous System/drug effects , Baroreflex/drug effects , Blood Pressure/drug effects , Diabetes Mellitus, Experimental/drug therapy , Heart Rate/drug effects , Niacinamide/therapeutic use , Animals , Autonomic Nervous System/physiology , Baroreflex/physiology , Blood Pressure/physiology , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/mortality , Heart Rate/physiology , Male , Niacinamide/pharmacology , Rats , Rats, Wistar , Survival Rate/trends , Vitamin B Complex/pharmacology , Vitamin B Complex/therapeutic use
2.
Sci Rep ; 11(1): 3593, 2021 02 11.
Article in English | MEDLINE | ID: mdl-33574570

ABSTRACT

Multiple animal and human studies have shown that administration of GLP-1RA can enhance ß-cell recovery, reduce insulin dosage, reduce HbA1c content in the blood, reduce the risk of hypoglycemia and reduce inflammation. In the NOD mouse model, peptide VP treatment can prevent and treat type 1 diabetes through immunomodulation. Therefore, we designed a new dual-functional PGLP-1-VP, which is expected to combine the anti-inflammatory effect of PGLP-1 and the immunomodulatory effect of VP peptide. In streptozotocin-induced hyperglycemic mice model, we demonstrated that PGLP-1-VP can act as a GLP-1R agonist to improve hyperglycemia and increase insulin sensitivity. In the NOD mouse model, PGLP-1-VP treatment reduced morbidity, mortality, and pancreatic inflammation, and showed superior effect to PGLP-1 or VP treatment alone, confirming that PGLP-1-VP may act as a dual-function peptide. PGLP-1-VP provided immunomodulatory effect through increasing Th2 cell percentage and balancing the ratio of Th2/Th1 in spleen and PLN, similar to P277 and VP. Additionally, PGLP-1-VP and PGLP-1 act the anti-inflammation by increasing Treg cells and TGF-ß1 content like DPP-IV inhibitor. Taken together, our data shows that the dual-functional PGLP-1-VP reduces morbidity and mortality in the NOD model, suggesting a potential role in preventing and treating type 1 diabetes.


Subject(s)
Diabetes Mellitus, Experimental/genetics , Glucagon-Like Peptide 1/analogs & derivatives , Glucagon-Like Peptide-1 Receptor/genetics , Inflammation/genetics , Peptide Fragments/genetics , Transforming Growth Factor beta1/genetics , Animals , Anti-Inflammatory Agents/metabolism , B-Lymphocytes/immunology , Diabetes Mellitus, Experimental/immunology , Diabetes Mellitus, Experimental/mortality , Diabetes Mellitus, Experimental/pathology , Disease Models, Animal , Glucagon-Like Peptide 1/genetics , Glucagon-Like Peptide 1/immunology , Humans , Immunomodulation , Inflammation/immunology , Inflammation/mortality , Mice , Peptide Fragments/immunology
3.
Biochim Biophys Acta Mol Basis Dis ; 1866(8): 165807, 2020 08 01.
Article in English | MEDLINE | ID: mdl-32353614

ABSTRACT

OBJECTIVES: Investigation of the effect of SGLT2 inhibition by empagliflozin on left ventricular function in a model of diabetic cardiomyopathy. BACKGROUND: SGLT2 inhibition is a new strategy to treat diabetes. In the EMPA-REG Outcome trial empagliflozin treatment reduced cardiovascular and overall mortality in patients with diabetes presumably due to beneficial cardiac effects, leading to reduced heart failure hospitalization. The relevant mechanisms remain currently elusive but might be mediated by a shift in cardiac substrate utilization leading to improved energetic supply to the heart. METHODS: We used db/db mice on high-fat western diet with or without empagliflozin treatment as a model of severe diabetes. Left ventricular function was assessed by pressure catheter with or without dobutamine stress. RESULTS: Treatment with empagliflozin significantly increased glycosuria, improved glucose metabolism, ameliorated left ventricular diastolic function and reduced mortality of mice. This was associated with reduced cardiac glucose concentrations and decreased calcium/calmodulin-dependent protein kinase (CaMKII) activation with subsequent less phosphorylation of the ryanodine receptor (RyR). No change of cardiac ketone bodies or branched-chain amino acid (BCAA) metabolites in serum was detected nor was cardiac expression of relevant catabolic enzymes for these substrates affected. CONCLUSIONS: In a murine model of severe diabetes empagliflozin-dependent SGLT2 inhibition improved diastolic function and reduced mortality. Improvement of diastolic function was likely mediated by reduced spontaneous diastolic sarcoplasmic reticulum (SR) calcium release but independent of changes in cardiac ketone and BCAA metabolism.


Subject(s)
Benzhydryl Compounds/pharmacology , Diabetes Mellitus, Experimental/drug therapy , Diabetic Cardiomyopathies/drug therapy , Glucosides/pharmacology , Hypoglycemic Agents/pharmacology , Sodium-Glucose Transporter 2 Inhibitors/pharmacology , Sodium-Glucose Transporter 2/genetics , Amino Acids, Branched-Chain/blood , Animals , Calcium-Calmodulin-Dependent Protein Kinase Type 2/antagonists & inhibitors , Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics , Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism , Clinical Trials as Topic , Diabetes Mellitus, Experimental/genetics , Diabetes Mellitus, Experimental/mortality , Diabetes Mellitus, Experimental/pathology , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/mortality , Diabetes Mellitus, Type 2/pathology , Diabetic Cardiomyopathies/genetics , Diabetic Cardiomyopathies/mortality , Diabetic Cardiomyopathies/pathology , Diet, High-Fat/adverse effects , Glucose/metabolism , Humans , Ketone Bodies/blood , Male , Mice , Mice, Transgenic , Ryanodine Receptor Calcium Release Channel/genetics , Ryanodine Receptor Calcium Release Channel/metabolism , Sarcoplasmic Reticulum/drug effects , Sarcoplasmic Reticulum/metabolism , Sarcoplasmic Reticulum/pathology , Sodium-Glucose Transporter 2/metabolism , Survival Analysis , Ventricular Function, Left/drug effects , Ventricular Function, Left/physiology
4.
J Nutr Biochem ; 68: 79-90, 2019 06.
Article in English | MEDLINE | ID: mdl-31030170

ABSTRACT

This study investigated if calcineurin/nuclear factor of activated T cells (NFAT) axis mediates the cardiac apoptosis in rats with type 1 diabetes mellitus (T1DM)-induced rats or administered chronically high-fat diet rich in corn oil (CO-HFD). Also, it investigated the impact of chronic administration of CO-HFD on Fas/Fas ligand (Fas/FasL)-induced apoptosis in the hearts of T1DM-induced rats. Adult male Wistar rats (140-160 g) were classified as control: (10% fat) CO-HFD: (40% fat), T1DM, and T1DM + CO-HFD (n=20/each). In vitro, cardiomyocytes were cultured in either low glucose (LG) or high glucose (HG) media in the presence or absence of linoleic acid (LA) and other inhibitors. Compared to the control, increased reactive oxygen species (ROS), protein levels of cytochrome C, cleaved caspase-8 and caspase-3, myocardial damage and impeded left ventricular (LV) function were observed in the hearts of all treated groups and maximally in T1DM + CO-HFD-treated rats. mRNA of all NFAT members (NFAT1-4) were not affected by any treatment. CO-HFD or LA significantly up-regulated Fas levels in both LVs and cultured cardiomyocytes in a ROS dependent mechanism and independent of modulating intracellular Ca2+ levels or calcineurin activity. T1DM or hyperglycemia significant up-regulated mRNA and protein levels of Fas and FasL by activating Ca2+/calcineurin/NFAT-4 axis. Furthermore, Fas/FasL cell death induced by recombinant FasL (rFasL) or HG media was enhanced by pre-incubating the cells with LA. In conclusion, activation of the Ca2+/calcineurin/NFAT4 axis is indispensable for hyperglycemia-induced Fas/FasL cell death in the cardiomyocytes and CO-HFD sensitizes this by up-regulation of Fas.


Subject(s)
Diabetes Mellitus, Experimental/pathology , Diet, High-Fat/adverse effects , Myocardium/metabolism , Myocardium/pathology , Animals , Calcineurin/metabolism , Cell Death , Cells, Cultured , Corn Oil/adverse effects , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/mortality , Diabetes Mellitus, Type 1/etiology , Diabetes Mellitus, Type 1/metabolism , Diabetes Mellitus, Type 1/mortality , Diabetes Mellitus, Type 1/pathology , Fas Ligand Protein/genetics , Fas Ligand Protein/metabolism , Gene Expression Regulation , Hyperglycemia/metabolism , Hyperglycemia/pathology , Linoleic Acid/pharmacology , Male , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , NFATC Transcription Factors/genetics , NFATC Transcription Factors/metabolism , Rats, Wistar , Reactive Oxygen Species/metabolism , fas Receptor/genetics , fas Receptor/metabolism
5.
J Oleo Sci ; 67(4): 463-470, 2018.
Article in English | MEDLINE | ID: mdl-29607889

ABSTRACT

Diabetes is a disease characterized not only by a high blood glucose level but also by high ketone levels. Medium chain triacylglycerols (MCT) are known as functional lipids, but they are rapidly metabolized to produce ketone bodies. In this study, we examined the effects of MCT intake on the pathological condition and energy bioavailability of diabetic animals. Streptozotocin (STZ)-induced diabetic rats were used as animal models for type I diabetes. The pathological condition was estimated through blood biochemical values, and the energy expenditure was calculated based on the respiratory quotient, which was analyzed using a mass spectrometer.Eight-week-old male STZ-induced diabetic Wistar rats were prepared and fed soybean oil (LCT) or MCT diets for 60 days. The survival rate of rats fed the MCT diet was higher than that of rats fed the LCT diet, although no ameliorating effects in the blood biochemical values were observed. In rats fed the LCT diet, their energy expenditure was much higher than their energy intake, whereas the energy balance was approximately equal in rats fed the MCT diet.These results indicated that energy bioavailability may contribute, at least in part, to the high survival rates in the diabetic MCT group, although MCT intake did not definitely improve the pathological condition of the experimental rats.


Subject(s)
Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/pathology , Dietary Fats/administration & dosage , Energy Metabolism , Triglycerides/administration & dosage , Administration, Oral , Animals , Diabetes Mellitus, Experimental/mortality , Disease Models, Animal , Male , Rats, Wistar , Streptozocin , Survival Rate
6.
J Diabetes Res ; 2017: 9035038, 2017.
Article in English | MEDLINE | ID: mdl-28804725

ABSTRACT

Meprins are membrane-bound and secreted metalloproteinases consisting of α and/or ß subunits that are highly expressed in kidney epithelial cells and are differentially expressed in podocytes and leukocytes (macrophages and monocytes). Several studies have implicated meprins in the progression of diabetic nephropathy (DN) and fibrosis-associated kidney disease. However, the mechanisms by which meprins modulate DN are not understood. To delineate the role of meprins in DN, we subjected meprin αß knockout (αßKO) mice and their wild-type (WT) counterparts to streptozotocin-induced type 1 diabetes. The 18-week survival rates were significantly lower for diabetic meprin αßKO mice when compared to those for their WT counterparts. There were significant decreases in mRNA and protein levels for both meprin α and ß in diabetic WT kidneys. Furthermore, the blood urea nitrogen levels and urine albumin/creatinine ratios increased in diabetic meprin αßKO but not in diabetic WT mice, indicating that meprins may be protective against diabetic kidney injury. The brush border membrane levels of villin, a meprin target, significantly decreased in diabetic WT but not in diabetic meprin αßKO kidneys. In contrast, isoform-specific increases in cytosolic levels of the catalytic subunit of PKA, another meprin target, were demonstrated for both WT and meprin αßKO kidneys.


Subject(s)
Diabetes Mellitus, Experimental/genetics , Diabetes Mellitus, Type 1/genetics , Diabetic Nephropathies/genetics , Metalloendopeptidases/genetics , Animals , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/mortality , Diabetes Mellitus, Experimental/pathology , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 1/mortality , Diabetes Mellitus, Type 1/pathology , Diabetic Nephropathies/mortality , Diabetic Nephropathies/pathology , Kidney Failure, Chronic/genetics , Kidney Failure, Chronic/mortality , Kidney Failure, Chronic/pathology , Kidney Function Tests , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mortality , Severity of Illness Index , Streptozocin
7.
Neuroreport ; 28(6): 319-324, 2017 Apr 12.
Article in English | MEDLINE | ID: mdl-28257395

ABSTRACT

Our previous studies showed that direct injury to the sciatic nerve (chronic constriction injury or axotomy) is associated with a numerical increase in synaptic number in the rat spinal dorsal horn. The aim of this study was to determine whether painful diabetic neuropathy (PDN) was also associated with numerical changes in the synaptic or neuronal numbers in the spinal dorsal horn. Overall, 17 adult SD rats were allocated randomly into the control group (n=5) and the streptozotocin (STZ) group (n=12). STZ was injected intraperitoneally to induce diabetes. In the STZ group, seven rats (STZ-H) showed hyperglycemia (fasting blood glucose >11.1 mM) and the rest of the five rats (STZ-N) did not. Rats were fed and observed for 28 days after hyperglycemia. Two of the seven STZ-H rats died of infection during the observation period. Body weight and paw withdraw threshold (PWT) decreased in the rest of the five STZ-H rats. Twenty-eight days after hyperglycemia, the L5 segment of the spinal cord was removed; paraffin-embedded sections were prepared and stained with Nissl's method and synaptophysin immunohistochemistry, respectively. The optical dissector (a stereological technique) was used to estimate the numbers of neurons and synapses in the spinal dorsal horn. Compared with the control group, the synaptic number and ratio between the numbers of synapses and neurons in the L5 segment of the spinal dorsal horn were increased significantly in the STZ-H rats (P<0.05), whereas the neuronal number did not change significantly (P>0.05). Parameters of STZ-N rats showed no significant changes. In conclusion, PDN, a form of neuropathic pain, is also associated with a synaptic plasticity (numerical increase) in the spinal dorsal horn. This numerical change might be the reason for central sensitization resulting in reduced pain threshold, enhanced responsiveness, and expanded receptive fields associated with PDN. Therefore, our studies indicate that neuropathic pain conditions with different etiologies might show the same synaptic numerical plasticity changes.


Subject(s)
Diabetes Mellitus, Experimental/pathology , Diabetic Neuropathies/pathology , Posterior Horn Cells/pathology , Synapses/pathology , Animals , Cell Count , Diabetes Mellitus, Experimental/mortality , Diabetes Mellitus, Experimental/physiopathology , Diabetic Neuropathies/mortality , Diabetic Neuropathies/physiopathology , Immunohistochemistry , Lumbar Vertebrae , Male , Pain Threshold , Random Allocation , Rats, Sprague-Dawley
8.
Nat Commun ; 7: 12021, 2016 06 21.
Article in English | MEDLINE | ID: mdl-27323847

ABSTRACT

Regulatory T cells (Tregs) are essential to suppress unwanted immunity or inflammation. After islet allo-transplant Tregs must migrate from blood to allograft, then via afferent lymphatics to draining LN to protect allografts. Here we show that Tregs but not non-Treg T cells use lymphotoxin (LT) during migration from allograft to draining LN, and that LT deficiency or blockade prevents normal migration and allograft protection. Treg LTαß rapidly modulates cytoskeletal and membrane structure of lymphatic endothelial cells; dependent on VCAM-1 and non-canonical NFκB signalling via LTßR. These results demonstrate a form of T-cell migration used only by Treg in tissues that serves an important role in their suppressive function and is a unique therapeutic focus for modulating suppression.


Subject(s)
Diabetes Mellitus, Experimental/therapy , Graft Rejection/immunology , Islets of Langerhans Transplantation , Lymphotoxin alpha1, beta2 Heterotrimer/immunology , Lymphotoxin beta Receptor/immunology , T-Lymphocytes, Regulatory/immunology , Transendothelial and Transepithelial Migration/immunology , Animals , Diabetes Mellitus, Experimental/genetics , Diabetes Mellitus, Experimental/immunology , Diabetes Mellitus, Experimental/mortality , Endothelial Cells/cytology , Endothelial Cells/immunology , Gene Expression Regulation , Graft Rejection/genetics , Graft Rejection/pathology , Graft Survival/genetics , Islets of Langerhans/immunology , Islets of Langerhans/surgery , Lymph Nodes/cytology , Lymph Nodes/immunology , Lymphatic Vessels/cytology , Lymphatic Vessels/immunology , Lymphotoxin alpha1, beta2 Heterotrimer/genetics , Lymphotoxin beta Receptor/genetics , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , NF-kappa B/genetics , NF-kappa B/immunology , Signal Transduction , Survival Analysis , T-Lymphocytes, Regulatory/cytology , Transplantation, Homologous , Vascular Cell Adhesion Molecule-1/genetics , Vascular Cell Adhesion Molecule-1/immunology
9.
Niger J Clin Pract ; 19(4): 480-5, 2016.
Article in English | MEDLINE | ID: mdl-27251964

ABSTRACT

BACKGROUND: The aim of this study was to investigate effects of α-tocopherol and/or insulin on the number of gingival inducible nitric oxide synthase (iNOS) positive cells in rats with experimental periodontitis with or without streptozotocin (STZ)-induced diabetes. MATERIALS AND METHODS: A total of 60 Sprague-Dawley rats were divided into three groups: Group I: The group without diabetes; Group II: The group with STZ-induced diabetes; Group III: The group with STZ-induced diabetes receiving insulin therapy. All animals received anesthesia, and 3/0 silk suture was inserted around the mandibular molar teeth. All groups were divided into subgroups receiving saline (Groups IA, IIA, IIIA) and α-tocopherol injection (Groups IB, IIB, IIIB). After a period of 3 weeks, all rats were sacrificed, and the number of gingival iNOS positive cells was analyzed using image analysis software. RESULTS: Applying α-tocopherol suppressed the number of gingival iNOS positive cells in Groups IB, IIB, and IIIB compared to application of saline (Groups IA, IIA, and IIIA) (P < 0.05). Numbers of gingival iNOS positive cells were found to be similar in the Groups I and III (P > 0.05). CONCLUSIONS: Within limitations of the current study, this is the first study one may suggest that α-tocopherol may reduce oxidative damage in the gingiva of the rats with periodontitis with or without STZ-induced diabetes and increase effects of insulin.


Subject(s)
Diabetes Mellitus, Experimental , Gingiva/drug effects , Nitric Oxide Synthase Type II/metabolism , Periodontitis , alpha-Tocopherol/pharmacology , Animals , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/mortality , Insulin/therapeutic use , Periodontitis/complications , Periodontitis/metabolism , Rats
10.
Cell Death Dis ; 7: e2233, 2016 05 19.
Article in English | MEDLINE | ID: mdl-27195679

ABSTRACT

Diabetes is a chronic disease that results from the body's inability to properly control circulating blood glucose levels. The loss of glucose homoeostasis can arise from a loss of ß-cell mass because of immune-cell-mediated attack, as in type 1 diabetes, and/or from dysfunction of individual ß-cells (in conjunction with target organ insulin resistance), as in type 2 diabetes. A better understanding of the transcriptional pathways regulating islet-cell survival is of great importance for the development of therapeutic strategies that target ß-cells for diabetes. To this end, we previously identified the transcription factor Myt3 as a pro-survival factor in islets following acute suppression of Myt3 in vitro. To determine the effects of Myt3 suppression on islet-cell survival in vivo, we used an adenovirus to express an shRNA targeting Myt3 in syngeneic optimal and marginal mass islet transplants, and demonstrate that suppression of Myt3 impairs the function of marginal mass grafts. Analysis of grafts 5 weeks post-transplant revealed that grafts transduced with the shMyt3 adenovirus contained ~20% the number of transduced cells as grafts transduced with a control adenovirus. In fact, increased apoptosis and significant cell loss in the shMyt3-transduced grafts was evident after only 5 days, suggesting that Myt3 suppression sensitizes islet cells to stresses present in the early post-transplant period. Specifically, we find that Myt3 suppression sensitizes islet cells to high glucose-induced cell death via upregulation of the pro-apoptotic Bcl2 family member Bim. Taken together these data suggest that Myt3 may be an important link between glucotoxic and immune signalling pathways.


Subject(s)
Bcl-2-Like Protein 11/genetics , Diabetes Mellitus, Experimental/genetics , Glucose/toxicity , Insulin-Secreting Cells/metabolism , Islets of Langerhans Transplantation , Transcription Factors/genetics , Adenoviridae/genetics , Adenoviridae/metabolism , Animals , Bcl-2-Like Protein 11/agonists , Bcl-2-Like Protein 11/metabolism , Cell Death/drug effects , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/mortality , Diabetes Mellitus, Experimental/therapy , Female , Gene Expression Regulation , Glucose/metabolism , Glucose Tolerance Test , Insulin-Secreting Cells/cytology , Insulin-Secreting Cells/drug effects , Mice , Mice, Inbred C57BL , Primary Cell Culture , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Signal Transduction , Streptozocin , Survival Analysis , Transcription Factors/antagonists & inhibitors , Transcription Factors/metabolism , Transplantation, Isogeneic
11.
J Biochem Mol Toxicol ; 30(9): 438-46, 2016 Sep.
Article in English | MEDLINE | ID: mdl-27079868

ABSTRACT

Recent evidence highlighted that there is a link between type-1 diabetes mellitus and histone deacetylases (HDACs) due to their involvement in beta-cell differentiation, proliferation, and function. The present study aimed to investigate the protective role of valproic acid (VPA) on beta-cell proliferation, function, and apoptosis in juvenile diabetic rat. Diabetes was induced in juvenile Sprague-Dawley rats by streptozotocin (75 mg/kg, i.p.) and VPA was administered at the doses of 150 and 300 mg/kg/day for 3 weeks by oral route. Various biochemical parameters, cellular alterations, and protein expression as well as apoptosis were assessed using different assays. VPA treatment significantly decreased plasma glucose, beta-cell damage, and apoptosis as well as increased the beta-cell function, insulin level/expression. The present study demonstrated that VPA improves beta-cell proliferation and function as well as reduces beta-cell apoptosis through HDAC inhibition. Our findings provide evidence that VPA may be useful for the treatment of juvenile diabetes.


Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylases/genetics , Hypoglycemic Agents/pharmacology , Insulin-Secreting Cells/drug effects , Valproic Acid/pharmacology , Animals , Apoptosis/drug effects , Blood Glucose/metabolism , Cell Proliferation/drug effects , Diabetes Mellitus, Experimental/genetics , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/mortality , Diabetes Mellitus, Type 1/drug therapy , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/metabolism , Diabetes Mellitus, Type 1/pathology , Disease Models, Animal , Drug Administration Schedule , Gene Expression Regulation , Glycated Hemoglobin/metabolism , Histone Deacetylases/metabolism , Histones/genetics , Histones/metabolism , Homeostasis , Humans , Insulin/biosynthesis , Insulin/genetics , Insulin-Secreting Cells/metabolism , Insulin-Secreting Cells/pathology , Male , Rats , Rats, Sprague-Dawley , Streptozocin , Survival Analysis
12.
J Gerontol A Biol Sci Med Sci ; 71(7): 850-7, 2016 07.
Article in English | MEDLINE | ID: mdl-26442901

ABSTRACT

We examined the effect of rapamycin on the life span of a mouse model of type 2 diabetes, db/db mice. At 4 months of age, male and female C57BLKSJ-lepr (db/db) mice (db/db) were placed on either a control diet, lacking rapamycin or a diet containing rapamycin and maintained on these diets over their life span. Rapamycin was found to reduce the life span of the db/db mice. The median survival of male db/db mice fed the control and rapamycin diets was 349 and 302 days, respectively, and the median survival of female db/db mice fed the control and rapamycin diets was 487 and 411 days, respectively. Adjusting for gender differences, rapamycin increased the mortality risk 1.7-fold in both male and female db/db mice. End-of-life pathological data showed that suppurative inflammation was the main cause of death in the db/db mice, which is enhanced slightly by rapamycin treatment.


Subject(s)
Diabetes Mellitus, Experimental , Diabetes Mellitus, Type 2 , Inflammation/pathology , Longevity , Sirolimus , Animals , Cause of Death , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/mortality , Diabetes Mellitus, Experimental/pathology , Diabetes Mellitus, Experimental/physiopathology , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/mortality , Diabetes Mellitus, Type 2/pathology , Diabetes Mellitus, Type 2/physiopathology , Female , Immunosuppressive Agents/metabolism , Immunosuppressive Agents/pharmacology , Longevity/drug effects , Longevity/physiology , Male , Mice , Mice, Inbred C57BL , Mortality , Sex Factors , Sirolimus/metabolism , Sirolimus/pharmacology , Treatment Outcome
13.
J Appl Physiol (1985) ; 119(6): 656-62, 2015 Sep 15.
Article in English | MEDLINE | ID: mdl-26183482

ABSTRACT

The purpose of this study was to compare the effects of aerobic, resistance, or combined exercise training on cardiovascular autonomic control and mortality in diabetic ovariectomized rats. Female Wistar rats were divided into one of five groups: euglycemic sedentary (ES), diabetic ovariectomized sedentary (DOS), diabetic ovariectomized aerobic-trained (DOTA), diabetic ovariectomized resistance-trained (DOTR), or diabetic ovariectomized aerobic+resistance-trained (DOTC). Arterial pressure (AP) was directly recorded and baroreflex sensitivity was evaluated by heart rate responses to AP changes. Cardiovascular autonomic modulation was evaluated by spectral analyses. No differences were observed in body weight and glycemia between diabetic rats. Animals in the DOTC and DOTA groups exhibited an increase in running time, whereas animals in the DOTC and DOTR groups showed greater strength. Trained groups exhibited improvement in total power and the high-frequency band of pulse interval and reduced mortality (vs. DOS). Animals in the DOTC (bradycardic and tachycardic responses) and DOTA (tachycardic responses) groups exhibited attenuation in baroreflex dysfunction that was observed in DOS and DOTR animals, and an improvement in AP variance. In conclusion, all training protocols led to reduced mortality, which may be due to an increase in physical capacity and to cardiovascular and autonomic benefits following training, regardless of any improvement in glycemic control. In this model, the aerobic and combined trainings seem to promote additional cardiovascular autonomic benefits when compared with resistance training alone.


Subject(s)
Autonomic Nervous System/physiopathology , Cardiovascular System/physiopathology , Diabetes Mellitus, Experimental/mortality , Diabetes Mellitus, Experimental/physiopathology , Physical Conditioning, Animal/physiology , Animals , Baroreflex/physiology , Blood Pressure/physiology , Female , Heart/physiopathology , Heart Rate/physiology , Ovariectomy/methods , Rats , Rats, Wistar , Resistance Training/methods
14.
Cell Transplant ; 24(8): 1555-70, 2015.
Article in English | MEDLINE | ID: mdl-25198179

ABSTRACT

Type 1 diabetes mellitus is caused by T-cell-mediated autoimmune destruction of pancreatic ß-cells. Systemic administration of mesenchymal stem cells (MSCs) brings about their incorporation into a variety of tissues with immunosuppressive effects, resulting in regeneration of pancreatic islets. We previously showed that human MSCs isolated from Wharton's jelly (WJ-MSCs) represent a potential cell source to treat diabetes. However, the underlying mechanisms are unclear. The purpose of this study was to discern whether undifferentiated WJ-MSCs can differentiate into pancreatic insulin-producing cells (IPCs) and modify immunological responses in nonobese diabetic (NOD) mice. Undifferentiated WJ-MSCs underwent lentiviral transduction to express green fluorescent protein (GFP) and then were injected into the retro-orbital venous sinus of NOD mice. Seven days after transplantation, fluorescent islet-like cell clusters in the pancreas were apparent. WJ-MSC-GFP-treated NOD mice had significantly lower blood glucose and higher survival rates than saline-treated mice. Systemic and local levels of autoaggressive T-cells, including T helper 1 cells and IL-17-producing T-cells, were reduced, and regulatory T-cell levels were increased. Furthermore, anti-inflammatory cytokine levels were increased, and dendritic cells were decreased. At 23 days, higher human C-peptide and serum insulin levels and improved glucose tolerance were found. Additionally, WJ-MSCs-GFP differentiated into IPCs as shown by colocalization of human C-peptide and GFP in the pancreas. Significantly more intact islets and less severe insulitis were observed. In conclusion, undifferentiated WJ-MSCs can differentiate into IPCs in vivo with immunomodulatory effects and repair the destroyed islets in NOD mice.


Subject(s)
Diabetes Mellitus, Experimental/therapy , Insulin-Secreting Cells/cytology , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/cytology , T-Lymphocytes/immunology , Wharton Jelly/cytology , Animals , Autoimmunity , Blood Glucose/analysis , C-Peptide/blood , Cell Differentiation , Cells, Cultured , Cytokines/genetics , Cytokines/metabolism , Diabetes Mellitus, Experimental/mortality , Diabetes Mellitus, Experimental/pathology , Female , Humans , Insulin/blood , Insulin-Secreting Cells/metabolism , Male , Mice , Mice, Inbred NOD , Survival Rate , T-Lymphocytes/cytology , T-Lymphocytes/metabolism
15.
Cell Transplant ; 24(8): 1599-1614, 2015.
Article in English | MEDLINE | ID: mdl-24612609

ABSTRACT

The role of the novel costimulatory molecule TIM4 in anti-islet response is unknown. We explored TIM4 expression and targeting in Th1 (BALB/c islets into C57BL/6 mice) and Th2 (BALB/c islets into Tbet(-/-) C57BL/6 mice) models of anti-islet alloimmune response and in a model of anti-islet autoimmune response (diabetes onset in NOD mice). The targeting of TIM4, using the monoclonal antibody RMT4-53, promotes islet graft survival in a Th1 model, with 30% of the graft surviving in the long term; islet graft protection appears to be mediated by a Th1 to Th2 skewing of the immune response. Differently, in the Th2 model, TIM4 targeting precipitates graft rejection by further enhancing the Th2 response. The effect of anti-TIM4 treatment in preventing autoimmune diabetes was marginal with only minor Th1 to Th2 skewing. B-Cell depletion abolished the effect of TIM4 targeting. TIM4 is expressed on human B-cells and is upregulated in diabetic and islet-transplanted patients. Our data suggest a model in which TIM4 targeting promotes Th2 response over Th1 via B-cells. The targeting of TIM4 could become a component of an immunoregulatory protocol in clinical islet transplantation, aiming at redirecting the immune system toward a Th2 response.


Subject(s)
Autoimmunity , Islets of Langerhans Transplantation/immunology , Membrane Proteins/metabolism , Th2 Cells/immunology , Adult , Animals , B-Lymphocytes/cytology , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Cell Differentiation , Cytokines/analysis , Cytokines/metabolism , Diabetes Mellitus, Experimental/mortality , Diabetes Mellitus, Experimental/surgery , Diabetes Mellitus, Type 1/surgery , Female , Graft Survival/immunology , Humans , Islets of Langerhans/pathology , Male , Membrane Proteins/genetics , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Inbred NOD , Middle Aged , Survival Rate , Th1 Cells/cytology , Th1 Cells/immunology , Th1 Cells/metabolism , Th2 Cells/cytology , Th2 Cells/metabolism , Transcriptome , Transplantation, Homologous
16.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 45(4): 691-5, 2014 Jul.
Article in Chinese | MEDLINE | ID: mdl-25286701

ABSTRACT

OBJECTIVE: To identify conditions that may improve the successful rate of STZ-induced rat models of diabetes mellitus (DM). METHODS: 100 male SD rats were randomly divided into control group (n = 10) and experimental group (n = 90). Rats in the experimental group were treated with intraperitoneal injection of STZ 65 mg/kg once, and were then categorized into succeeded DM model group and failed group. Their body masses and levels of fasting blood glucose (FBG), urine glucose (UG), urine protein (UP), urine routine, renal function, liver function, blood lipids and kidney hypertrophy index (KHI) were monitored and compared. Dead rats were dissected to observe diseased organs. Pathological changes of those diseased organs were examined by HE staining. RESULTS: DM rat models were established through a single intraperitoneal injection of STZ, with a success rate of 58.89%. During the experiment, 43.33% of rats died. Compared with the rats in the failed group, the DM rat models had significantly higher levels of body mass, food intake, water intake, urine output, FBG, creatinine, blood urea nitrogen, KHI, urinary tract infections, and mortality; but lower levels of total protein, albumin and cholesterol and triglyceride (P < 0.05). Nine rats died of pulmonary edema; 19 died of renal abscess. The causes of 11 dead rats were not clear. CONCLUSION: DM rat models can be established through a single intraperitoneal injection of STZ 65 mg/kg, but with high mortality rate. The deaths may be associated with infection, malnutrition, suffocation of lymphatic circulation, toxicity of STZ, and changes in environmental and climate conditions.


Subject(s)
Diabetes Mellitus, Experimental/mortality , Animals , Cause of Death , Kidney/physiopathology , Male , Rats , Rats, Sprague-Dawley
17.
Am J Transplant ; 14(7): 1533-42, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24909185

ABSTRACT

Establishment of noninvasive and efficient islet transplantation site together with the avoidance of immunosuppressive drugs for islet engraftment is currently the two major tasks for islet transplantation approach to treat patients with type 1 diabetes. Here, we proposed a method to achieve long-term allogeneic islet graft function without immunosuppression after transplantation in subcutaneous sites. Two agarose rods with basic fibroblast growth factor and heparin were implanted for 1 week in dorsal subcutaneous sites in diabetic rats. After rod removal, 1500 islets were transplanted into the prevascularized pockets. Islets transplanted in prevascularized but not nontreated subcutaneous sites rapidly reverted hyperglycemia in all streptozotocin-induced diabetic rats. In contrast to transient normalization of blood glucose when allogeneic islets were transplanted into liver, allogeneic islets transplanted into this prevascularized subcutaneous site demonstrated long-term graft survival and function in all three rat strain combinations (Fisher 344 to ACI, Lewis to ACI and Fisher 344 to Wistar), evidenced by nonfasting blood glucose level, plasma insulin concentration, intraperitoneal glucose tolerance test and immunohistochemistry. These results indicated that a subcutaneous site prevascularized by this method is potentially a suitable site for successful allogeneic islet transplantation without immunosuppression.


Subject(s)
Diabetes Mellitus, Experimental/therapy , Fibroblast Growth Factor 2/administration & dosage , Graft Survival/physiology , Heparin/administration & dosage , Islets of Langerhans Transplantation , Neovascularization, Physiologic , Subcutaneous Tissue/blood supply , Animals , Blood Glucose/metabolism , Diabetes Mellitus, Experimental/mortality , Glucose Tolerance Test , Insulin/metabolism , Male , Rats , Rats, Inbred ACI , Rats, Inbred Lew , Rats, Wistar , Subcutaneous Tissue/metabolism
18.
PLoS One ; 9(1): e86838, 2014.
Article in English | MEDLINE | ID: mdl-24466263

ABSTRACT

BACKGROUND: Recent animal study and clinical trial data suggested that remote limb ischemic postconditioning (RIPostC) can invoke potent cardioprotection. However, during ischemia reperfusion injury (IR), the effect and mechanism of RIPostC on myocardium in subjects with or without diabetes mellitus (DM) are poorly understood. Autophagy plays a crucial role in alleviating myocardial IR injury. The aim of this study was to determine the effect of RIPostC on mice myocardial IR injury model with or without DM, and investigate the role of autophagy in this process. METHODOLOGY AND RESULTS: Streptozocin (STZ) induced DM mice model and myocardial IR model were established. Using a noninvasive technique, RIPostC was induced in normal mice (ND) and DM mice by three cycles of ischemia (5 min) and reperfusion (5 min) in the left hindlimb. In ND group, RIPostC significantly reduced infarct size (32.6±3.0% in ND-RIPostC vs. 50.6±2.4% in ND-IR, p<0.05) and improved cardiac ejection fraction (49.70±3.46% in ND-RIPostC vs. 31.30±3.95% in ND-IR, p<0.05). However, in DM group, no RIPostC mediated cardioprotetion effect was observed. To analyze the role of autophagy, western blot and immunohistochemistry was performed. Our data showed that a decreased sequestosome 1 (SQSTM1/p62) level, an increased Beclin-1 level, and higher ratio of LC3-II/LC3-I were observed in ND RIPostC group, but not DM RIPostC group. CONCLUSIONS: The current study suggested that RIPostC exerts cardioprotection effect on IR in normal mice, but not DM mice, and this difference is via, at least in part, the up-regulation of autophagy.


Subject(s)
Autophagy , Cardiotonic Agents , Diabetes Mellitus, Experimental/pathology , Disease Models, Animal , Hindlimb/blood supply , Ischemic Preconditioning, Myocardial , Myocardial Reperfusion Injury/prevention & control , Animals , Blotting, Western , Diabetes Mellitus, Experimental/mortality , Echocardiography , Immunoenzyme Techniques , Male , Mice , Mice, Inbred C57BL , Myocardial Reperfusion Injury/mortality , Myocardial Reperfusion Injury/pathology , Survival Rate
19.
J Immunol ; 191(3): 1373-82, 2013 Aug 01.
Article in English | MEDLINE | ID: mdl-23817413

ABSTRACT

Type 1 diabetes enhances susceptibility to infection and favors the sepsis development. In addition, diabetic mice produced higher levels of histamine in several tissues and in the blood after LPS stimulation than nondiabetic mice. In this study, we aimed to explore the role of mast cells (MCs) and histamine in neutrophil migration and, consequently, infection control in diabetic mice with mild sepsis (MS) induced by cecum ligation and puncture. We used female BALB/c, MC-sufficient (WB/B6), MC-deficient (W/W(v)), and NOD mice. Diabetic mice given MS displayed 100% mortality within 24 h, whereas all nondiabetic mice survived for at least 5 d. The mortality rate of diabetic mice was reduced to 57% after the depletion of MC granules with compound 48/80. Moreover, this pretreatment increased neutrophil migration to the focus of infection, which reduced systemic inflammatory response and bacteremia. The downregulation of CXCR2 and upregulation of G protein-coupled receptor kinase 2 in neutrophils was prevented by pretreatment of diabetic mice given MS with compound 48/80. In addition, blocking the histamine H2 receptor restored neutrophil migration, enhanced CXCR2 expression, decreased bacteremia, and improved sepsis survival in alloxan-induced diabetic and spontaneous NOD mice. Finally, diabetic W/W(v) mice had neutrophil migration to the peritoneal cavity, increased CXCR2 expression, and reduced bacteremia compared with diabetic WB/B6 mice. These results demonstrate that histamine released by MCs reduces diabetic host resistance to septic peritonitis in mice.


Subject(s)
Diabetes Mellitus, Experimental/mortality , G-Protein-Coupled Receptor Kinase 2/metabolism , Mast Cells/immunology , Neutrophils/metabolism , Receptors, Interleukin-8B/metabolism , Alloxan , Animals , Bacteremia/drug therapy , Cell Movement , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/microbiology , Down-Regulation/drug effects , Female , Histamine/metabolism , Histamine H2 Antagonists , Inflammation/drug therapy , Mice , Mice, Inbred BALB C , Mice, Inbred NOD , Receptors, Histamine H2/metabolism , Sepsis/complications , Sepsis/microbiology , Sepsis/mortality , Up-Regulation/drug effects , p-Methoxy-N-methylphenethylamine/pharmacology
20.
J Clin Invest ; 123(3): 1262-74, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23426181

ABSTRACT

Diabetes increases oxidant stress and doubles the risk of dying after myocardial infarction, but the mechanisms underlying increased mortality are unknown. Mice with streptozotocin-induced diabetes developed profound heart rate slowing and doubled mortality compared with controls after myocardial infarction. Oxidized Ca(2+)/calmodulin-dependent protein kinase II (ox-CaMKII) was significantly increased in pacemaker tissues from diabetic patients compared with that in nondiabetic patients after myocardial infarction. Streptozotocin-treated mice had increased pacemaker cell ox-CaMKII and apoptosis, which were further enhanced by myocardial infarction. We developed a knockin mouse model of oxidation-resistant CaMKIIδ (MM-VV), the isoform associated with cardiovascular disease. Streptozotocin-treated MM-VV mice and WT mice infused with MitoTEMPO, a mitochondrial targeted antioxidant, expressed significantly less ox-CaMKII, exhibited increased pacemaker cell survival, maintained normal heart rates, and were resistant to diabetes-attributable mortality after myocardial infarction. Our findings suggest that activation of a mitochondrial/ox-CaMKII pathway contributes to increased sudden death in diabetic patients after myocardial infarction.


Subject(s)
Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism , Diabetes Mellitus, Experimental/enzymology , Myocardial Infarction/enzymology , Sinoatrial Node/enzymology , Animals , Apoptosis , Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics , Cardiac Output , Cells, Cultured , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/mortality , Female , Fibrosis , Heart Rate , Humans , In Vitro Techniques , Male , Mice , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Knockout , Mitochondria, Heart/metabolism , Myocardial Infarction/etiology , Myocardial Infarction/mortality , Myocardium/enzymology , Myocardium/pathology , Oxidation-Reduction , Oxidative Stress , Peptides/pharmacology , Reactive Oxygen Species/metabolism , Sinoatrial Node/pathology , Sinoatrial Node/physiopathology
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